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An increased number of replaced embryos counteracts the adverse effect of hydrosalpinges on IVF/ET outcome

The relationship between the number of replaced embryos and the outcome of IVF-ET in patients with hydrosalpinges was investigated in a retrospective, nonrandomized study performed at a governmental IVF center. One hundred patients undergoing 161 IVF
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  Journal  of  Assisted Reproduction  and  Genetics, Vol.  15, No. 1,  1998 CLINIC L  ASSISTED  REPRODUCTION An Increased Number  of  Replaced Embryos Counteracts  the Adverse  Effect  of  Hydrosalpinges  on  IVF/ET  Outcome KARIM HASSANEIN ISMAIL ABD-EL-MAEBOUD, 1,2,4  ESSAM AL-DEIN M. KHALIFA, 1,3  andEL-SIR EL-HUSSEIN 1 Submitted: April  14,  1997 Accepted: July 2,  1997 Purpose The  relationship between  the  number  of  replacedembryos  and the  outcome  of  IVF-ET  in  patients with hydro-salpinges was investigated in a retrospective, nonrandom-iied  study performed  at a  governmental  IVF  center. Methods One  hundred patients undergoing  161 IVF  cycles ending in  embryo  transfer  were studied. Previously diag-nosed  hydrosalpinges  were evident on transvaginal sonogra- phy in 48  cycles  in 26  patients  group  I) and not  evident  in15  cycles  in 10  patients  group  II .  The  control group included  98 cycles in 64 patients with tubal lesions otherthan hydrosalpinx. Pregnancy and implantation rates were the  main outcome measures. Results Replacement  of  three or fewer embryos was associ- ated  with  significantly  lower implantation rates  in  group  I compared  to  controls. Despite  the  difference  in the  rank  of IVF  trial within the same group,  significantly  lower implan-tation rates were found when four or fewer embryos were replaced in the  control group  and not in  group  I.  onclusion An increased number of  replaced  embryoscounteracts  the  adverse  effe t  of  hydrosalpinges  on  IVF/ET outcome. INTRODUCTION Tubal-factor  infertility  is one of the classical indica- tions for in  vitro fertilization/embryo transfer  (IVF/ 1  Infertility/IVF  Center,  King  Fahd  Specialist Hospital, Buraidah, KSA. 2  Department  of  Obstetrics  and  Gynecology,  Ain  Shams University, Cairo,  Egypt. 3  Department  of  Obstetrics  and  Gynecology, Assuit University,Assuit, Egypt. 4  To  whom correspondence should  be  addressed  at  Department of  Obstetrics  and Gynecology, Ain  Shams University, Abbassia, Cairo, Egypt. ET) treatment. Tubal factor is not an entity per se  but, rather, a heterogeneous group with  different  anatomi-cal, pathologic, and etiologic factors. Recent retrospec-tive studies suggest that the  presence  of unilateral orbilateral hydrosalpinx has an adverse  effect  on implan-tation and pregnancy rates following IVF/ET therapy (1-5).  The mechanism for this negative influence onIVF/ET outcome  is not yet  fully  understood. Simulta- neous  endometrial  damage  during  the  acute-phase damage of the tubes (1,2), with a  role  for  Chlamydiatrachomatis  infection,  was  suggested  (3).  The  mostaccepted explanation  is  that  the  tubal  fluid,  drainedinto the uterine cavity, may hinder implantation (6) through  toxic (1,3,7), mechanical, or dilutional (3) effects.  Therefore, tubal ligation, salpingostomy  (1),  or salpingectomy  (2-5,7)  was  suggested  to be  performedprior to IVF therapy. Many  factors are known to influence success afterIVF, such as the age of the patient  (8,9),  the rank ofthe IVF trial  (9),  and the number of replaced embryos (10,11).  We conducted a  retrospective  analysis  of theIVF/ET  results  in our  unit  for  women with known tubal-factor  infertility to investigate the relationbetween the number of replaced embryos and the  out- come of IVF/ET in patients with a unilateral or bilat-eral hydrosalpinx. M TERI LS  ND  METHODS The records of all patients undergoing IVF/ET ther- apy  at the Infertility/IVF Center, King Fahd SpecialistHospital, El-Qassim, Saudi Arabia, between January1993 and November  1996  were retrospectively  ana- lyzed.  After  exclusion of couples with  severe  male factor,  endometriosis, and previous surgical treatment of  hydrosalpinges in women <40 years  old,  thereremained records of 100 women with definite tubal 1058-0468/98/0100-0022 15.00/0  ©  1998  Plenum  Publishing  Corporation   KEY  WORDS in  vitro fertilization; infertility; hydrosalpinx; embryo  transfer; implantation rate.  HYDROSALPINX AND  NUMBER  OF  REPLACED EMBRYOS 23 lesion.  In  these  patients  161  treatment  cycles  ending in  embryo transfer were scrutinized. The tubal lesions for  these women were diagnosed by both hysterosal- pingography and  laparoscopy  or laparotomy,  with  36 of  them diagnosed  to  have  uni-  or  bilateral hydrosal-pinges.On transvaginal sonography (TVS), the demonstra-tion of uni- or bilateral hydrosalpinges on basal exami-nation on day 2 of the cycle or their developmentduring ovulation induction  (12)  was  recorded.  Ahydrosalpinx was defined as an echo-free tubular or fusiform  cystic structure located adjacent to the ovary,along with other criteria  as  discussed  by  Tessler  et al. (13).  The  study cycles were divided into three groups.Group I: 48 cycles in 26 patients with hydrosal-pinges evident,  at  least once,  on  TVS. Group II: 15 cycles in 10 patients with hydrosal-pinges, not evident on any occasion on repeated TVS.Group  III  (control  group):  98  cycles  in 64  patients with  tubal lesions other than hydrosalpinges. The  stimulation protocols used were either long-term buserelin  (LTB)  or  short-term buserelin  (STB) and  human menopausal gonadotrophin (hMG). Stan- dard  IVF  techniques were  used  in all  cases.  A  maxi-mum of  five  embryos was replaced. Clinical pregnancy was  defined  as the  presence  of a  gestational  sac on ultrasound or by documenting trophoblastic tissue inpathology specimens  from  abortions  or  ectopic preg-nancies.  The  presence  of  ectopic pregnancy  or the  lossof a clinical pregnancy before 12 weeks was considered an  early pregnancy loss. Ongoing pregnancy  was defined  as  reaching  a  gestational duration  of >12 weeks.  The  implantation rate  was  calculated  as the ratio between implanted  and  transferred embryos,  tak- ing into consideration the number of intrauterine  gesta- tional  sacs  and assuming the implantation of oneembryo in the  case  of  ectopic  pregnancy.Statistical analysis was performed using Student's t  test  and the  Mann-Whitney  U  test  as  appropriate.  A P  value of  <0.05  was considered significant. RESULTS The  three  groups were comparable in terms of  age, rank of trial, induction protocols, and number of hMGampoules used (Table  I).  Compared  to the  other groups,group I had  significantly  higher numbers of retrievedoocytes and replaced embryos. However, the implanta-tion and clinical pregnancy rates were lower, with nostatistical significance. All pregnancies were intrauter-ine, with only one heterotopic pregnancy (2.4 ) ingroup  III,  ending in abortion and salpingectomy. Also,three pregnancies ended in midtrimester abortion ingroup  III. The transfer of more than three embryos in groupsI and III was associated with a significantly higherrank of IVF trial (Table  II).  On transfer of three or fewer  embryos, group  I had  lower clinical  and  ongoingimplantation rates compared to the controls. Also, themultiple pregnancy rate was lower and the differenceapproached statistical significance  P  =  0.084).  In group  III,  the transfer of more than three embryos wasassociated with significantly lower implantation  rates. On the other hand, the  transfer  of more than threeembryos group I was associated with a similar clinicalpregnancy rate,  with  insignificantly increased, ratherthan  decreased, rates  of  ongoing  and  multiple pregnan- cies  and clinical and ongoing implantations. DISCUSSION Reviewing  our data as a whole, we failed to  find any  significant adverse  effect  of  hydrosalpinges  on IVF/ET  outcome, which  contradicts  the  findings  of other studies  (2-5).  This  is not  likely explained  by confounding  factors, which were comparable to those of  other reports, including  the  sample size  (1,3,5),  the long acquisition time  for  patients  (3-5),  and the use of  more  than  one  stimulation protocol (2,4). Despite limiting  the number of replaced embryos to a maxi-mum of three in some studies (1,5), the numbers ofreplaced embryos  in all  study groups  in  different reports were  found  to be  comparable  (1-5).  On the contrary, a  significantly  increased number of embryos was  replaced  in  patients with hydrosalpinx evidenton TVS in the present study. This may be attributedpartially to the increased number of retrieved oocytes in  this group of patients, also observed by other investi-gators (3). The finding of more cycles ending in replac- ing  four  or more embryos in this group might havebeen responsible for counteracting the unfavorableconditions for the implantation  process.  Supporting this  assumption  is the  finding  that,  on  replacement  of three  or  fewer embryos,  the  presence  of a  hydrosalpinxon  TVS,  despite being associated with better ovarianresponsiveness, with more retrieved oocytes andreplaced embryos, was  associated  with significantlylower clinical and ongoing implantation rates  com- pared to those of controls. This was also associated with  a reduction in the multiple pregnancy rate. In thisgroup, the implantation rate was approximately  one- third  that of the controls, which agrees with the find- Journal  of  Assisted Reproduction  and  Genetics, Vol.  15, No. 1,  1998  24 ABD-EL-MAEBOUD, KHALIFA,  AND  EL-HUSSEIN Table I.  Outcome  of IVF  Cycles a No. of patientsNo. of transfers Age b Rank of  trial b STB simulation protocol c No. of hMG ampoules b No. of  retrieved oocytes/cycle b No. of embryos/transfer*Replacement  of >4  embryos c Clinical  pregnancy  rate/ET c Early  pregnancy  loss c Ongoing pregnancy rate c Rate of multiple pregnancy c Per-embryo clinical implantation rate c Per-embryo ongoing implantation rate c Group  I(hydrosalpinx evident  on  TVS) 26 48 31.3  ± 3.9 1.96  ±  1.03*13/48 (27.1)37.3  ±  10.9 10  ± 3.8 a,b 3.7  ±  0.7 c,d 30/48  (62.5) b,e 10/48 (20)3/10 (30)7/10 (70)3/10 (30)14/179 (7.8)**11/179(6.2)Group II (hydrosalpinx not evident  on  TVS) 10 15 29.9  ± 3.8 1.4  ± 0.63* 3/15 (20)37.7  ±  18.3 7  ±  3.6 a 2.8 ±  1.3 c 5/15  (33.3) e 6/15 (40) 3/6  (50) 3/6  (50) 1/6  (16.7)7/42 (16.7)**4/42 (9.5)Group  III (controls) 64 98 32.1  ± 5.3 1.93  ±  1.83 23/98  (23.5)38.3  ±  12 7.6  ±  4.6 b 3.1  ± l d 35/98  (35.7) b 26/98  (26.5)5/26(19.2)21/26  (80.8) 10/26 (38.5) 38/303  (12.5) 32/303  (10.6) a  Values within rows with  the  same superscript  are  significantly different  at  P <  0.01 (a),  0.005  (b), 0.001 (c), 0.001 (d),  and  0.05 (e). b  Values  are  means  ± SD. c  Values in parentheses are percentages. *  P  =  0.0524. **  P =  0.079. ings  of  other investigators (2-4) reporting  a  similarreduction  in  implantation  rates  (2.93  to  4.21 , com-pared to 10.27 to 11.53 in the controls). In contrast,we found no difference in the pregnancy rate, in agree-ment with the findings of one other study (5). However,other investigators (1-4) reported  a  significant decrease  in  pregnancy  rates  (10.1  to  19.2 , versus  23to 37 in the  controls). Different  confounding variables could have created the  bias  in the  results  in the  present study. However, the  nature of such studies truly makes randomizationimpossible, which negates  the  value  of a  prospective study  design. The study groups might be influenced by  the availability of embryos and the patients'  choice, with  those with  a  higher rank  of IVF  trial being more willing  to  accept replacement  of  more embryos (11). It  is our policy to  replace  four or  five  embryos in theolder patient group  or  those with  a  history  of  failed implantation  after a previous  IVF/ET  attempt. In thecontrol group, transfer  of  more  than  three  embryos Table  II.  Effect  of  Number  of  Embryos Replaced  on  IVF/ET Outcome a No. of transfersAge b Rank of  trial b No. of embryos/transfer b Clinical  pregnancy  rate/ET c Early  pregnancy loss c Ongoing pregnancy rate c Rate  of  multiple pregnancy c Per-embryo clinical implantation rate c Per-embryo ongoing implantation rate c Group  I  (hydrosalpinx  on  TVS)Subgroup A (<3  embryos transferred) 18 30.8  ± 3.8 1.56  ±  0.92 a 2.94  ±  0.24 c,d 4/18 (22.2)2/4 (50) 2/4  (50) 0/4 (0)* , ** 5/53 (7.5) a 2/53 (3.8) b Subgroup B (>4  embryos transferred) 30 31.4  ± 4.2 2.2  ±  1.03 a 4.2  ±  0.41 d 6/30 (20)1/6(16.7) 5/6  (83.3) 3/6  (50)* 10/126  (7.9) 9/126(7.1) Group III (controls)Subgroup A (<3  embryostransferred) 63 31.5  ± 5.5 1.6  ±  1.36 b 2.47  ±  0.67 k,k 19/63  (30.2) 3/19 (15.8) 16/19  (84.2)9/19  (47.4)**30/156  (19.2) a,d 26/156 (16.7) b,d Subgroup  B (>4  embryostransferred) 35 33.2  ± 4.7 2.51  ± 2.38 b 4.2 ± 0.4 l e 7/35 (20) 2/7  (28.6)5/7 (71.4) 1/7  (14.3)8/147 (5.4) d 6/147(4.1) da Values  within  rows with the same superscript are significantly  different  at  P <  0.05 (a), 0.02 (b), 0.01 (c), 0.001 (d), and 0.001 (e). b  Values  are  means  ± SD. c  Values in parentheses are percentages. *P =  0.109.**  P =  0.084. Journal  of  Assisted Reproduction  and  Genetics, Vol.  15, No. 1,  1998  HYDROSALPINX AND NUMBER OF REPLACED EMBRYOS 25 failed to  counteract  the  adverse  effect  of  these  two factors on implantation rates. On the contrary, preg- nancy  and implantation rates were not lowered onreplacement  of  more  than  three embryos  in  patients with  hydrosalpinges evident on TVS. Actually, these findings  were not expected in view of the expectedadditional adverse  effect  of hydrosalpinx  (1-5).  These findings strengthen our  theory that  an  increased num-ber of replaced embryos counteracts the  adverse  effect of  hydrosalpinx  on  IVF/ET  outcome.  In  fact,  transfer  of more embryos was also recently suggested to improvesuccess rates  in  patients with unexplained repeated IVF  failure  (11).An  increased incidence  of  pregnancy  loss  in  associa- tion with hydrosalpinx was reported, due mainly tobiochemical pregnancies (3). Confirming the  findings of other investigators  (4,5),  we  found  no difference inthe early pregnancy  loss.  Also, there was no increase in  the incidence of  ectopic  pregnancies, in agreement with  other studies  (2-4). The  presence  of persistent tubal distention appearsto be crucial in exerting an adverse  effect  on IVF/EToutcome.  In the  present study,  the  transfer  of  fewerembryos  in the  patients with hydrosalpinges  not  evi-dent on TVS was associated  with  pregnancy and implantation  rates  comparable to those of the controls.This agrees with the  findings  of Strandell et al. (1), who  found  that  an  adverse  effect  on IVF  outcome  was present only in  cases  with marked persistent distention of  the hydrosalpinges. Moreover, the significant decrease  in IVF therapy outcome observed by us andother investigators (2-4) was  found  only in patients with  hydrosalpinges evident  on  ultrasonography.  In fact,  considering  all  patients with hydrosalpinges  as one group  (5,14,15)  might have been responsible for the  failure  to  recognize  any  adverse  effect  on IVF pregnancy outcome in some of these studies (14,15). Various  surgical  approaches  were  suggested  to nor-malize  IVF/ET  pregnancy rates  for  this group  of patients  (1-5,7).  The  suggestion that salpingectomyresults  in a  reduction  of  ovarian vascularization  with stimulation and  formation  of  follicular cysts  (1) is denied by other investigators (3). Moreover, a recent study  showed that bilateral salpingectomy has no detri- mental  effect  on the  ovarian response  or the  outcomeof therapy (16). The role of sonographically guided puncture  before stimulation  for IVF  (17,18) needs  tobe  evaluated.  Our  results show  that  an  increased num- ber of  replaced embryos might  be  beneficial  in  counter- acting the  adverse  effect  of  hydrosalpinx  on  IVF/EToutcome. The implantation and pregnancy rates mightbe improved through increased chances of embryos to escape  the mechanical, dilutional, or even toxic  effect of  the tubal fluid drained into the uterine cavity. A  potential hazard  of  multiple embryo replacement is  the  expected increase  in  multiple pregnancy rates. In the  present study, replacement  of  more  embryos  in patients with hydrosalpinges on TVS was associated with an  overall multiple pregnancy rate  of  30 ,  two sets of twins and one triplet, of 10 pregnancies, com-pared to 7.3 , only  three  sets of twins, of a total of 41  pregnancies reported in three studies  (3-5).  So itappears that the presence of hydrosalpinges on TVS is  associated with lower prospects of becoming preg- nant  or of having a multiple pregnancy. Patients with repeated  unexplained  IVF  seem  to  have  similar pros-pects.  Replacement of more embryos in these patientswas associated with an increased pregnancy rate, with  a slight increase in the rate of multi- fetal  pregnancy (11). Twin gestations are usually ade-quately managed and  fetal  wastage remains low com-pared to high-order multiple gestations. The need for flexibility  in  the  number  of  replaced embryos  and a compromise between the highest possible pregnancy rate  and the lowest frequency of high-risk, high-order multiple  pregnancies is evident (10,11,19). The pres- ence  of hydrosalpinx on TVS appears to be one of  these exceptional circumstances (19) where the transfer of four  or more embryos may be  justified  to optimize IVF-ET outcome. Reviewing the data of other investigators with  larger  series  of IVF cycles seems worthwhile toallow elaboration of this assumption. Proved to be ofvalue, an increased number of replaced embryos inpatients with hydrosalpinges might  offer  an  optionalalternative to surgical measures with their knownhazards. REFERENCES   Strandell  A,  Waldenstrm  U,  Nilsson  L,  Hamberger  L:  Hydrosal- pinx  reduces  in-vitro  fertilization/embryo transfer pregnancyrates. Hum Reprod  1994;9:86l-863 2. 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